Methods for the preparation of 4-hydroxy benzothiophene

ABSTRACT

The present invention is concerned with a novel process for the preparation of the hydroxybenzothiophene of formula I                    
     comprising cyclocarbonylation of a compound of formula II                    
     wherein Y is as defined in the specification, followed by saponification. The compound of Formula I is a building block of pharmaceutically active substances, e.g. 5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-7-benzothiophenylmethyl]-2,4-thiazolidinedione and the corresponding sodium salt which are from agents useful in the treatment of diabetes.

This application is DIV of Ser. No. 09/625,887 filed Jul. 26, 2000.

BACKGROUND OF THE INVENTION

Methods for the preparation of 4-hydroxybenzothiophene have beendescribed by Iwasaki et al. (1991) J. Org. Chem. 1991. 56, 1922. Here acyclocarbonylation of a primary allylacetate is performed in presence ofa high catalyst loading. Further, this process is characterized by atleast five process steps which in part require extreme reactionconditions. Therefore, a simpler more efficient process utilizing lessprocess steps has been long desired.

SUMMARY OF INVENTION

The present invention is concerned with a novel process for thepreparation of benzothiophene derivatives, especially with thepreparation of 4-hydroxybenzothiophene. 4-Hydroxybenzothiophene is abuilding block for pharmaceutically active compounds, e.g.5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-7-benzothiophenylmethyl]-2,4-thiazolidinedione.This compound is known in the art and is described for example inInternational Patent Application WO 94/27995. It is especially usefulfor prophylaxis and treatment of diabetes mellitus type I and II.

Surprisingly it has been found that using the process according to thepresent invention 4-hydroxybenzothiophene can be prepared with lessprocess steps under moderate conditions with an outstanding yield.

DETAILED DESCRIPTION

In accordance with this invention, a new procedure is provided forpreparing 4-hydroxybenzothiophene having the formula

from a compound of

wherein

Y is halogen or —OR; and

—OR is an aryloxy group or a group of formulae —(CO)—R′, —O—(CO)—O—R″,or —O—(PO)—(OR″)₂, wherein R′ is alkyl, perfluoro-C₁₋₂₀-alkyl, aryl, R″is alkyl, aryl or benzyl;

which comprises cyclocarbonylating the compound of formula II byreacting, in an organic solvent medium containing a carboxylic acidanhydride and a base, the compound of formula II with carbon monoxide inthe presence of a carbonylation catalyst capable of complexing withcarbon monoxide to produce the carboxylic acid ester of the compound offormula I as a reaction product and thereafter saponifying this reactionproduct to produce the compound of formula I above.

The cyclocarbonylation is carried out by introducing carbon monoxideinto the reaction medium containing the compound of formula II above anda carbonylation catalyst capable of complexing with carbon monoxide toproduce the carboxylic acid ester of the compound of formula I as areaction product. The saponification step is carried out after thisreaction product is formed. The saponification is carried out by addinga base to the reaction medium so that the pH is raised to any value offrom 8 to 14.

Surprisingly, it has been found that using the process of thisinvention, the 4-hydroxybenzothiophene can be prepared with less processsteps under moderate conditions and with an outstanding yield. Theprocess also provides an efficient cyclocarbonylation reaction undermild conditions in a single reaction medium so that the startingmaterial for this reaction, i.e., the compound of formula II, does nothave to be purified such as by distillation but can be used as crudematerial. Therefore, this process provides an efficientcyclocarbonylation reaction under mild conditions. In addition,substrates for the cyclocarbonylation reaction (compound of Formula II)do not need to be purified, e.g. by distillation, but can be used as“crude” material.

According to the present invention, the term “cyclocarbonylation” refersto an introduction of a carbonyl group by means of carbon monoxide gascoupled with the formation of a cyclic ring structure.

The term “saponification” refers to the hydrolysis of an ester underbasic conditions.

The term “transition metal compound” refers to a metal-phosphine complexcompound wherein the term metal refers to Pd, Pt, Ru, Co, Rh or Ni,preferably Pd.

The term “ligand” refers to phosphine, arsine or stibine derivatives,preferable phosphine derivatives, of general formulae P(R¹)(R²)(R³),(R¹)(R²)P—(X)—P(R¹)(R²), As(R¹)(R²)(R³) or Sb(R¹)(R²)(R³), preferablyP(R¹)(R²)(R³), wherein R¹, R², and R³ are defined below.

The term “alkyl” refers to a branched or straight chain monovalent alkylradical of one to nine carbon atoms (unless otherwise indicated),preferably one to four (lower) carbon atoms. This term is furtherexemplified by such radicals as methyl, ethyl, n-propyl, isopropyl,i-butyl, n-butyl, t-butyl and the like.

The term “aryl” refers to a monovalent carbocyclic aromatic radical,e.g. phenyl, optionally substituted, independently, with halogen,lower-alkyl, lower-alkoxy, lower-alkylenedioxy, carboxy, trifluoromethyland the like, with phenyl being especially preferred.

The term “lower alkanoic acid” refers to those lower alkanoic acidscontaining from 2 to 6 carbon acids such as propionic acid, acetic acid,etc.

The term “aryloxy”, signifies a group of the formula aryl-O— in whichthe term “aryl” has the significance given above. Phenyloxy is apreferred example of such an aryloxy group.

The term “alkoxy”, alone or in combination, signifies a group of theformula alkyl-O— in which the term “alkyl” has the significance givenabove, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec.butoxy and tertbutoxy, preferably methoxy and ethoxy.

The term “alkylenedioxy” refers to C₁₋₃-alkyl-dioxy groups, such asmethylenedioxy, ethylenedioxy or propylenedioxy.

The term “halogen” refers to fluorine, chlorine, and bromine.

In more detail, the present invention refers to a process for thepreparation of compounds of formula I

comprising cyclocarbonylation of a compound of formula II

wherein

Y is halogen or —OR;

—OR is an aryloxy group or a group of formulae —O—(CO)—R′, —O—(CO)—O—R″or —O—(PO)—(OR″)₂, wherein R′ is alkyl, perfluoro-C₁₋₂₀-alkyl, aryl, R″is alkyl, aryl or benzyl;

followed by saponification.

In a preferred embodiment of the invention, the cyclocarbonylationreaction is carried out in the presence of a base and the carbonylationcatalyst is a complex of a transition metal compound with a ligand.

In a preferred embodiment of this invention, the cyclocarbonylationreaction carried out in the presence of a base and a carboxylic acidanhydride, one utilizes a catalyst which is a transition metal compoundcomplexed with a ligand. Cyclocarbonylation reactions and theirconditions are known. Any of the conventional conditions utilized insuch cyclocarbonylation reactions can be utilized in accordance with theprocess of this invention.

In accordance with the process of this invention, thiscyclocarbonylation reaction is carried out in the presence of acarbonylation catalyst capable of complexing with carbon monoxide. Anyconventional carbonylation catalyst capable of complexing with carbonmonoxide can be utilized in accordance with this invention. Among thepreferred catalysts are those catalysts which are transition metalcompounds complexed with a ligand. Transition metal compounds useful forthe process of the present invention comprise salts of Pd, Pt, Ru, Co,Rh— or Ni and also include transition metals on an inert support such asPd/C. The use of transition metal compounds as catalysts has beendescribed for example in Matsuzaka et al. (1988) J. Org. Chem. 53, 3832.Preferred transition metal compounds are salts of palladium, e.g.Pd(OAc)₂, Pd₂dba₃, PdCl₂, Pd₂Cl₂(π-allyl)₂, PdCl₂(NCMe)₂,[PD(NCMe)₄](BF₄)₂, and most preferably Pd(OAc)₂. The mentioned catalystsare known in the art (e.g. U.S. Pat. No. 5,380,861; “Carbonylation,Direct Synthesis of Carbonyl Compounds”, H. M. Colquhoun, D. J.Thompson, M. V. Trigg, Plenum Press, 1991) and/or are commerciallyavailable (e.g. from Fluka, Buchs, Switzerland or Strem Chemicals, Kehl,Germany).

The ligand of the transition metal compound in the catalyst may beselected from a group consisting of phosphine, arsine or stibinederivatives, preferable phosphine derivatives of general formulaeP(R¹)(R²)(R³), (R¹)(R²)P—(X)—P(R¹)(R²), As(R¹)(R²)(R³) orSb(R¹)(R²)(R³), preferably P(R¹)(R²)(R³), wherein X, R¹, R², and R³ aredefined below.

Especially suitable ligands are chiral and non-chiral mono- anddiphosphorus compounds for example described in Houben-Weyl, “Methodender organischen Chemie”, vol. E1, page 106 et seq. Georg Thieme VerlagStuttgart, 1982, and Aspects Homog. Catal., 4, 145-202 (1981),especially those of the formulae

P(R¹)(R²)(R³) and (R¹)(R²)P—(X)—P(R¹)(R²)

wherein R¹, R² and R³ each independently are C₁₋₈-alkyl, cyclohexyl,benzyl, naphthyl, 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thiophenyl,2- or 3- or 4-pyridyl, phenyl or phenyl which is substituted byC₁₋₄-alkyl, C₁₋₄-alkoxy, halogen, trifluoromethyl, lower alkylydenedioxyor phenyl and X is binaphthyl, 6,6′-dimethyl- or6,6′-dimethoxybiphenyl-2,2′-diyl, or one of the groups —(CH₂)_(n)—,—CH₂CH₂—P(C₆H₅)—CH₂CH₂—,

and n is a number of 1-8.

Examples of suitable phosphorus ligands are shown in Scheme 1.

The most preferred phosphorus ligands are triphenylphosphine,

The preparation of a transition metal complex is explained in moredetail for the corresponding palladium-phosphine complex: Thepalladium-phosphine complex compound is conveniently formed in situ froma palladium component and a phosphine ligand. These palladium componentsis for example metallic palladium, which is optionally supported on acarrier material such as carbon, or a complex or a salt of 0-, 2- or4-valent palladium such as palladium-bis(dibenzylideneacetone),palladium chloride, palladium acetate and the like. For the in situpreparation, the phosphorus ligand/transition metal compound ratio(mol/mol; P/Pd) amounts to about 0.1:1 to 100:1, preferably to about 6:1to 15:1. Suitable phosphine ligands are for example chiral andnon-chiral mono- and diphosphorus compounds such as are described inHouben-Weyl, Methoden der organischen Chemie, volume E1, page 106 et.seq. Georg Thieme Verlag Stuttgart, 1982, and Aspects Homog. Catal., 4,145-202 (1981), especially those described above.

For the in situ preparation of the palladium-phosphine complex compoundpalladium-(II) chloride or palladium-(II) acetate,palladium-dichloro-bis(acetonitrile) and a bis(diphenylphosphino)alkanemaybe used.

Further, the process of the present invention comprises the use of basesfor the cyclocarbonylation reaction like tertiary bases such astri-alkyl-amines, di-alkyl-aryl-amines, pyridines, alkyl-N-piperidines,and for example inorganic bases such as NaOH, KOH or salts of carbonicacids. Examples are (alkyl)₃amines, e.g. triethylamine,ethyl-di-isopropyl-amine, pyridine, N-methyl-piperidine, sodium hydrogencarbonate, potassium hydrogen carbonate, di-sodium carbonate, etc. Thepreferred base is triethylamine. However, any base conventionally usedfor cyclocarbonylation can be used in the process of this invention.

Any conventional inert solvent can be used as the reaction medium.Solvents for the above reaction are known to skilled persons. Preferredsolvents are aromatic solvents, e.g. toluene, xylene, benzene,halogenated hydrocarbons, e.g. CH₂Cl₂, nitrites, e.g. acetonitrile,ester, e.g. ethylacetate, amides, e.g. DMF, ether, e.g. THF, dioxane,urethanes, e.g. TMU, sulfoxides, e.g. DMSO, and mixtures thereof Thepreferred solvent is toluene.

In carrying out the cyclocarbonylation reaction any of the conditionsconventionally employed in carrying out such reaction can be utilized inaccordance with this invention. This reaction is carried out so that onemole of carbon monoxide is reacted with one mole of the compound offormula II to produce the cyclocarbonylated reaction product whichreaction product is the carboxylic acid ester of the compound of formulaI. This reaction is carried out by introducing carbon monoxide into thereaction medium. In carrying out this reaction, usually a stoichiometricexcess of carbon monoxide is added to the reaction medium to ensurecomplete reaction. This is achieved by adjusting the pressure of thecarbon monoxide added. By utilizing the conventional reaction conditionsfor such cyclocarbonylation reaction, one achieves the formation of thereaction product of one mole of the carbon monoxide with one mole of thecompound of formula II above. The reaction product formed from thisreaction is not isolated from the reaction medium but is treated with abase to remove the ester group from the hydroxy moiety on the compoundof formula I and form the compound of formula I. In thecyclocarbonylation reaction, the temperature can vary between 40° C. and170° C., preferably between 60-120° C., and most preferably the reactionis performed at about 90° C. The substrate/catalyst ratio (mol/mol;S/Pd) amounts to 1 to 10000, preferably 100 to 5000, more preferably1000 to 2000 and most preferably 1200 to 1500. For the in situpreparation, the above mentioned phosphorus ligand/transition metalcompound ratio (mol/mol; P/Pd) amounts to 0.1:1 to 100:1, preferably 6:1to 15:1. The upper limit for the carbon monoxide (CO) pressure is onlylimited by the specification of the autoclave used. For the lowerpressure limit the carbonylation reaction would work even with a COpressure of 1 bar. Preferably, the CO pressure is about 20 to 70 bar,more preferably 35 to 60 bar.

The cyclocarbonylation reaction of this invention is carried out in thepresence of a base and a carboxylic acid anhydride to form thecarboxylic acid ester of the compound of formula I. Any conventionalcarboxylic acid anhydride can be used, particularly the aroic acidanhydrides and the lower alkanoic acid anhydrides. Among the preferredcarboxylic acid anhydrides are benzoic acid anhydride and acetic acidanhydride with acetic acid anhydride being particularly preferred. Thecarboxylic acid anhydride should be present in the reaction medium insufficient quantity to allow it to react, during the cyclocarbonylationreaction, with all of the compounds of formula II present in thisreaction medium. However, a stoichiometric excess of the carboxylic acidanhydride can be present in the reaction medium.

Surprisingly it has been found that the “crude” compound of Formula IIcan be used for the preparation of the compound of Formula I. Apreparation of a crude material is performed by collecting the compoundof Formula II, e.g. 1-(2-thienyl)allyl acetate, with an organic solventand drying without further purification. The preparation of thismaterial is exemplified in Example 1. Example 2 B shows the use of thecrude starting material for the preparation of the compound of FormulaI.

The cyclocarbonylation reaction is followed by saponification.Conditions for saponification reactions are known in the art anddescribed for example in “Practical Organic Chemistry”, A. I. Vogel,Longmans Ed., 1967, p. 390-393. In carrying the saponification reactionof the carboxylation acid ester of formula I, the reaction medium inwhich this reaction product is formed is treated with a base. Anyconventional base can be utilized. Normally, it is preferred to utilizethe alkali metal or alkaline earth metal bases such as alkali metal,hydroxides, alkoxides, etc. In a preferred embodiment of the presentinvention, the saponification is carried out in a biphasic mixture ofaqueous sodium hydroxide and toluene or in an homogeneous mixture ofsodium methylate in methanol.

Compounds of Formula II may be prepared by methods known in the art, forexample by reaction of a thiophene carbaldehyde of Formula III(illustrated in Scheme 2 a; commercially available, Fluka, Aldrich).

with a vinyl-metal-X reagent, with -metal-X being —MgCl, —MgBr, —MgI or—Li, preferably —MgCl or —MgBr, followed by reaction with an acidderivative. Other allyl compounds, e.g. the corresponding allylhalogenides or allyl trialkylammonium salts, are also suitable reagents.The acid derivative can be selected from a group consisting of compoundsof formulae, (R′—CO)₂O, R″O—(CO)—Cl, Cl—(PO)(OR″)₂, R′—(CO)-Hal whereinR′ is alky, perfluoro-C₁₋₂₀-alkyl, aryl, R″ is alkyl, aryl or benzyl andHal is Cl or Br. The preferred acid derivative is (R′—CO)₂O, and hereespecially the acetanhydride. The most preferred thevinyl-metal-X-reagents are vinylmagnesium chloride or vinylmagnesiumbromide.

In the most preferred embodiment of the present invention, the compoundof Formula II is prepared by reaction of vinylmagnesium chloridefollowed by reaction with acetanhydride as shown in scheme 2, varianta).

Additional methods for the preparation of compound III are summarized inscheme 2.

The compound of Formula I is usefull for the preparation ofpharmaceutically active substances, e.g.5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-7-benzothiophenylmethyl]-2,4-thiazolidinedioneand its salts, especially the corresponding sodium salt. A process forthe preparation of this compound has been described for example inInternational Patent Application WO 98/42704.

In addition, the compounds may be prepared according to the followingprocesses:

In a first step the compound of Formula I may be converted into4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole byreaction with a mesylate of Formula V

under basic conditions. The reaction may be performed in solvents likeDMF with for example sodium carbonate, potassium carbonate or cesiumcarbonate, preferably potassium carbonate; or in THF with KtBu; or intoluene and KOH with phase transfer catalysts.

The above process may be followed by a nitration reaction of4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole to give5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole.Normally nitric acid is used for the nitration reaction which may beperformed at room temperature to about 50° C., preferably roomtemperature.

The5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleobtained by the above process may be converted into of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleby hydrogenation. The conditions of the hydrogenation reaction (H₂/Raneynickel) are known in the art. Hydrogen pressure may be 1 to 10 bar,preferably 1 bar.

The above process may be continued by the reaction of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolewith HHal/NaNO₂ followed by reaction with CH═CHCOOCH₃/Cu(I)Hal, whereinHal is Br or Cl, preferably Br. The reaction product in case of Hal isBr ismethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate.

The reaction ofmethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionatewith thiourea will produce2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one.The reaction is normally performed in alkylalkohols like ethanol.

This compound(2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one)may then be converted into5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedioneby reaction under acid conditions. The reaction maybe performed at 1-4bar, preferably at 1 bar. Acidic conditions are provided by an organicor inorganic add in an appropriate solvent, e.g. HCl/ethanol.

The reaction maybe optionally continued by conversion of5-[4-[2-(5-methyl-2-phenyl-oxazole-4-6l)-ethoxy]-enzothiophene-7-methyl]-2,4-thiazolidinedionein a corresponding salt, preferably the sodium salt(5-[4-[2-(5-ethyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedioneby reaction under basic conditions, preferably with NaOH in THF.

A further embodiment of the invention comprises a process for thepreparation of5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedioneand/or of5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiphene-7-methyl]-2,4-thiazolidinedionesodium salt comprising

a) conversion of a compound of Formula I into4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole byreaction of a compound of Formula I

 with a mesylate of Formula V

 under basic conditions; followed by

b) nitration of4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole to give5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole;

c) hydrogenation of5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleto give5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole;followed by

d) reaction of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolewith HHal/NaNO₂ and CH═CHCOOCH₃/Cu(I)Hal, wherein Hal is Br or Cl togivemethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate;followed by

e) reaction ofmethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionatewith thiourea to give2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one;followed by

f) reaction of2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-oneunder acid conditions to give5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiopene-7-methyl]-2,4-thiazolidinedione;and

g) optionally followed by reaction of5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedioneunder basic conditions to give5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione.

The invention further comprises the use of any of the above describedprocesses for the preparation of5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-7-benzothiophenylmethyl]-2,4-thiazolidinedioneand5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione.

A further embodiment of the present invention comprises the compound5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione.

The following examples shall illustrate preferred embodiments of thepresent invention but are not intended to limit the scope of theinvention.

EXAMPLE 1 1-(2-Thienyl)allyl Acetate

A 1.5 l 4-necked glass flask equipped with a mechanical stirrer, athermometer and an argon inlet was charged with 112.2 g of2-thiophenecarbaldehyde (1.00 mol) and 100 ml of THF and to theresulting solution was added dropwise at −20° C. within 1.2 h 650 ml ofvinylmagnesium chloride 1.7 M solution in THF. The temperature duringthe addition was kept between −20 and −25° C. with aid of an acetone/dryice bath, then increased to 0° C. during 35 min and kept at thistemperature for 20 min. To the resulting brown suspension was added atca. 0° within 40 min 132.7 g of acetic anhydride (1.30 mol). The coolingbath was removed and after stirring for 1 h 400 ml of deionized waterwas added at 10-15° C. within 20 min. The biphasic yellow-brown mixturewas stirred for an additional 1 h at room temperature and transferred toa separatory funnel with aid of 500 ml of hexane. The brown aqueousphase was separated and extracted with 400 ml of hexane. The combinedorganic phases were washed with 3×200 ml deionized water, dried (Na₂SO₄,15 min stirring) and rotatory evaporated (T_(bath) 35°, 12 mbar, 1 h).Material of this quality is defined as “crude” and is also suitable forcyclocarbonylation (see Example 2 B). The orange-brown oil (199.7 g) wasdistilled in an apparatus consisting of a 500-ml two-neckedround-bottomed flask, a distillation head with water-cooling and afraction sampler. A forerun containing low-boiling components (yellowishoil) was collected at T_(head) between room temperature and 55° C. and0.5-0.6 mbar, the main fraction was collected at T_(head) of 59-62° C.(T_(pot) 63-67° C.) and 0.4 mbar.

Yield: 161.53 g (88.6%) of 1-(2-thienyl)allyl acetate as a slightlyyellow oil.

EXAMPLE 2 A 4-Hydroxybenzothiophene

An autoclave was charged under an argon flow with 27.34 g of1-(2-thienyl)allyl acetate (0.150 mol, distilled), 28.4 ml of aceticanhydride (30.6 g, 0.30 mol), 42.0 ml of triethylamine (30.7 g, 0.30mol), 23.6 mg of palladium acetate (0.105 mmol) and 0.264 g oftriphenylphosphine (1.00 mmol), all with aid of 53 ml of toluene. Thenthe autoclave was sealed, evacuated twice under slow stirring (150 rpm)to 0.2 bar and pressurized with 8 bar of argon, then pressurized threetimes with 20 bar of carbon monoxide and vented, and finally pressurizedwith 50 bar of carbon monoxide. The reaction mixture was stirred (500rpm) and heated at 120° C. and the carbonylation carried out at 50 barconstant total pressure for 6 h. After cooling, the autoclave was ventedand the CO atmosphere was exchanged by evacuating to ca. 0.2 bar andpressurizing 8 bar of argon four times. The resulting dark solution waspoured into a 0.5 l flask containing 120 ml of ice water and thebiphasic solution was stirred for 1 h at room temperature. The aqueousphase was extracted in a separatory funnel with 80 ml of toluene andthan the combined organic phases were washed with 3×30 ml, with a totalof 90 ml of deionized water and reduced to a total weight of 46 g byrotary evaporation (50° C./60 mbar).

The residue containing the crude acetate was transferred to a 0.35 lglass flask under argon with aid of 25 ml of toluene. After addition of82 ml of 4N sodium hydroxide (328 mmol) the mixture was stirredintensively (1200 rpm) at 50° for 1.5 h and then after coolingtransferred in a 0.5 l separatory funnel. After removal of the organiclayer, the dark aqueous phase was extracted with 80 ml of toluene andthe combined organic phases were back-extracted with 2×20 ml, a total of40 ml of deionized water. The combined aqueous phases were treated with1.0 g of charcoal, stirred at room temperature for 5 min under argon andfiltered through a Speedex layer. The filter cake was rinsed three timeswith 20 ml, a total of 60 ml of deionized water. The clear brown,combined phases were concentrated until no more toluene distilled, thenafter cooling to 5° C. in an ice bath 75 ml of 25% HCl were added underargon during 35 min, whereas the temperature was kept under 15° with aidof an ice bath. The resulting thick crystalline suspension was stirredfor 1 h in an ice bath (internal temperature 2-3° C.) and filtered on asintered glass filter. The filter cake was washed three times with 50ml, a total of 150 ml of ice-cold water and dried on the rotavapor at50° C./1 mbar to constant weight.

Yield: 18.9 g (84%) of 4-hydroxybenzothiophene

m.p. 76-78° C., content: 98%.

EXAMPLE 2 B 4-Hydroxybenzothiophene

An autoclave was charged under an argon flow with 27.34 g of1-(2-thienyl)allyl acetate (0.150 mol, crude quality, see Example 1),28.4 ml of acetic anhydride (30.6 g, 0.30 mol), 42.0 ml of triethylamine(30.7 g, 30 mol), 23.6 mg of palladium acetate (0.105 mmol) and 0.264 gof triphenylphosphine (1.00 mmol), all with aid of 53 ml of toluene.Then the autoclave was sealed, evacuated twice under slow stirring (150rpm) to 0.2 bar and pressurized with 8 bar of argon, then pressurizedthree times with 20 bar of carbon monoxide and vented, and finallypressurized with 50 bar of carbon monoxide. The reaction mixture wasstirred (500 rpm) and heated at 120° C. and the carbonylation carriedout at 50 bar constant total pressure for 6 h. After cooling, theautoclave was vented and the CO atmosphere was exchanged by evacuatingto ca 0.2 bar and pressurizing 8 bar of argon four times. The resultingdark solution was poured into a 0.5 l flask containing 120 ml of icewater and the biphasic solution was stirred for 1 h at room temperature.The aqueous phase was extracted in a separatory funnel with 80 ml oftoluene and then combined organic phases were washed with 3×30 ml, atotal of 90 ml of deionized water and reduced to a total weight of 46 gby rotary evaporation (50° C./60 mbar).

The residue containing the crude acetate was filtered through 17 g ofsilica gel (Ø=3 cm) and the filter washed with 150 ml of toluene. Thecombined organic phases were reduced to a total weight of 40 g by rotaryevaporation and transferred to a 0.35 l glass flask under argon with aidof 20 ml of toluene. After addition of 82 ml of 4N sodium hydroxide (328mmol) the mixture was stirred intensively (1200 rpm) at 50° for 1.5 hand then after cooling transferred in a 0.5 l separatory funnel. Afterremoval of the organic layer, the dark aqueous phase was extracted with80 mol of toluene and the combined organic phases were back-extractedwith 2×20 ml, a total of 40 ml of deionized water. The combined aqueousphases were treated with 1.0 g of charcoal, stirred at room temperaturefor 5 min under argon and filtered through a Speedex layer. The filtercake was rinsed three times with 20 ml, a total of 60 ml of deionizedwater. The clear brown, combined phases were concentrated until no moretoluene distilled, then after cooling to 5° C. in an ice bath 75 ml of25% HCl were added under argon during 35 min, whereas the temperaturewas kept under 15° with aid of an ice bath. The resulting thickcrystalline suspension was stirred for 1 h in an ice bath (internaltemperature 2-3° C.) and filtered on a sintered glass filter. The filtercake was washed three times with 50 ml, a total of 150 ml of ice coldwater and dried on the rotavapor at 50° C./1 mbar to constant weight.

Yield: 16.5 g (73%) of 4-hydroxybenzothiophene as brown crystals

m.p. 75-76° C., content: 95%.

EXAMPLE 3 Variation of Phosphorus Ligands

4.93 mg of palladium acetate and 57.57 mg of triphenylphosphine in 10 mlof toluene were stirred for 1 h in a glove-box (O₂<1 ppm). A 35 mlautoclave was charged with 0.40 g of distilled 1-(2-thienyl)allylacetate, 0.42 ml of acetanhydride, 0.62 ml of triethylamine and 1.0 mlof the catalyst solution described above. The autoclave was conditionedwith 30 bar of CO and pressurized with 70 bar of CO. Thecyclocarbonylation was carried out at 120° C. for 2 h. GC-analysisrevealed a conversion of 96% with a content of 4-acetoxybenzthiophene of91%.

A) EXAMPLES 3.1-3.6

According to Example 3, table 1 summarizes the following experimentswhich were performed with phosphorus ligands other thentriphenylphosphine.

TABLE 1 % con- % Content of Example P-ligand^(b)) version^(a))4-Acetoxybenzothiophene^(a)) 3.1 PPh(3,5-tBu-Ph)₂ 92 87 3.2P(3,5-tBu-Ph)₃ 93 88 3.3 AMPHOS 99 95 3.4 NMDPP 98 94 3.5 P(2-Furyl)₃ 9690 3.6 P(o-DMA-Ph)₃ ^(c)) 13 12 ^(a))Determined via GC (area-%).^(b))See structures in Scheme 1. ^(c))P/Pd = 2

B) EXAMPLES 3.7-3.23

The following additional examples 3.7 to 3.23 were performed withfurther phosphorus ligands. The reaction were performed according to thedescription given above. However, the autoclave was pressurized with 50bar CO and the cyclocarbonylation reaction was carried out at 90° C. for16-18 h.

TABLE 2 Example P/Pd % con- % Content No. P-Ligand^(b)) ^(c))version^(a)) ^(a)) 3.7  PPh(3,5-tBu-Ph)₂ 2 >99 94 3.8  P(3,5-tBu-Ph)₃2 >99 97 3.9  PAMP 2 >99 92 3.10 MOP 2 >99 92 3.11 P(2-Furyl)₃ 10  >9985 3.12 TROPP-Ph 6 >99 95 3.13 PPh(Diphol) 6 >99 88 3.14 (S,S)-DDPPI2 >99 92 3.15 DPEphos 2 99 40 3.16 DPPM 2 40 30 3.17 DIOP 4 99 72 3.18P(O-nC₄H₉)₃ 6 99 86 3.19 Diphol-DIOP 2 99 71 3.20 DPPF 2 >99 81 3.21TPP-ox-Ph 1 85 44 3.22 P(m-Tol)₃ 6 >99 83 3.23 P(n-Bu)₃ 6 95 70 ^(a))%Content of 4-acetoxybenzothiophene, determined via GC (Area %). ^(b))Seestructures in Scheme 1. ^(c))Phosphorus-to-palladium molar ratio.

EXAMPLE 4 Cyclocarbonylation Reactions: CO Pressure and S/Pd Ratio

6.0 g of distilled 1-(2-thienyl)allyl acetate were reacted for 4 h asdescribed in Example 2 A with 6.2 mg of palladium acetate 72.1 mg oftriphenylphosphine, 6.3 ml of acetanhydride and 9.3 ml of triethylaminepresent. GC-analysis revealed a conversion of 98% with a content ofe-acetoxybenzthiophene of 94%.

EXAMPLES 4.1-4.7

According to Example 4 table 2 summarizes experiments performed underdifferent reaction conditions (CO pressure and S/Pd ratio).

TABLE 2 Example % yield^(b)) No. P_(CO)[bar]^(a)) S/Pd T[° C.] 2 h 4 h 6h 4.1 70 1200 120 99 — — 4.2 70 ″ 100 90 98 n.d. 4.3 40 ″ 120 96 99 >99 4.4 20 ″ ″ 67 88 89 4.5 70 1500 ″ 97 >99  — 4.6 50 ″ ″ n.d. n.d. >99 4.7 40 ″ ″ 92 97 98 ^(a))determined at RT. ^(b))Determined via GC(area-%).

EXAMPLE 5 4-[2-(Benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole

218 g (1.45 mol) of 4-hydroxy-benzothiophene and 511 g (1.82 mol) ofmesylate of Formula V

were dissolved in 5.4 l of DMF, followed by addition of 555 g (4.02 mol)of potassium carbonate (dry). The reaction mixture was stirred at 100 to105° C. for 6 to 8 hours. The resulting suspension was cooled to 5° C.and 7 l of water was added. The suspension was stirred at 5° C. for 30minutes. The precipitate was filtered with suction and washed with 550ml of DMF/water (1:1) and 1.1 l water. The precipitate was stirred at 0to 5° C. in 1 l of MEK (methylethylketone) for 30 minutes. Then theprecipitate was filtered with suction and dried at 50° C.

Yield: 365 g (=75%)4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole.

m.p.126° C./129-131° C.

EXAMPLE 65-Methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole

286 g (0.853 mol) of4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole weresuspended in 6.3 l of glacial acetic acid. Temperature was raised to 60° C. The resulting clear solution was cooled to 25° C. 132 ml (3.18 mol)of 100% nitric acid were added within 3 minutes. The reaction mixturewas cooled below 30° C. After crystallization the suspension was stirredat 18 to 20° C. for 1 hour. The precipitate was filtered with suctionand washed with 2×600 ml of tert-butyl methyl ether. The residue wassuspended in 4 l of acetic ester for 15 minutes. 200 g (1.9 mol) ofsodium carbonate in 3 l water were added. The resulting suspension wasstirred for 1 hour. Acetic ester was distilled off followed by additionof 2 l of water. The suspension was stirred for 30 minutes. Theprecipitate was filtered with suction, washed with water and dried (50°C., 24 hours).

Yield: 210 g of5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole(=70%).

m.p. 149-151° C.

EXAMPLE 75-Methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole

50 g (1.052 mol) of5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolewere solved in 1 l of THF at 20 to 25 ° C. 75 ml Lewatit M 600(OH³¹-form) (Bayer AG) were washed with about 100 ml THF, added to the5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolesolution and stirred at room temperature for 1 hour. Then the Lewatit M600 material was filtered with suction and washed with 100 ml THF. 12.5g of Raney nickel were added to the combined THF solutions followed byhydrogenation of the5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleat standard pressure. The temperature of the reaction mixture should notexceed 35 to 40° C. Hydrogen pressure was increased to 6 bar within 6hours. After hydrogenation the reaction mixture was stirred for 1 hour.Then the catalyst was filtered with suction, the THF was distilled off,180 ml ethanol was added and the residue was boiled out for 30 minutes.The reaction mixture was stirred at 0° C. for 1 hour. The precipitatewas filtered with suction and the residue was washed with 25 ml ethanoland dried for 24 hours at 50° C. (vacuum).

Yield: 42.4 g of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole(=92%).

m.p. 122-126° C.

EXAMPLE 8Methyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate

320 g (0.91 mol) of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolewere solved in 6.4 l acetone. Within 30 sec one third of a 320 ml (2.74mol) of 48% HBr in 900 ml water were added. After cooling to 0 to 4° C.and crystallization the suspension was stirred at 0 to 4° C. for 1 hour.Then the remaining 48% HBr solution in water was added within 15 minutesat 0 to 4° C. and stirred at this temperature for 15 minutes followed byaddition of 63.9 g (0.93 mol) sodium nitrite in 180 ml water within 15minutes at 3 to 5° C. and stirring for 30 minutes at 3 to 5° C. 1230 mlof methacrylate CH═CHCOOCH₃ (13.6 mol) was added to this reactionmixture at 10 to 14° C. followed by addition of 3.2 g Cu(I)bromide.Temperature was increased to 20 to 25° C. within 30 minutes followed bystirring at this temperature for 1 hour and 10 minutes at 30° C. 1.8 lof water was added to the reaction mixture followed by distillation ofacetone/methacrylate CH═CHCOOCH₃ at a temperature of 40° C. The finalvolume was about 2 l. 1 l of water was added to separate the remainingmethacrylate CH═CHCOOCH₃. The final volume was about 2 l. The blackprecipitate was solved by addition of 4.5 l of acetic ester and stirringfor 15 minutes. The two phase reaction mixture was filtered and theaqueous phase was extracted with 2 l of acetic ester. After extractionwith 2 l of an aqueous 2% NaCl-solution the acetic ester solutions werecombined and distilled. 2 l of acetic ester was added to the residue andagain distilled. 3 l of ethanol were added to the residue and boiled. 15g of activated charcoal were added and stirred for 15 minutes. Afterfiltration and cooling to room a precipitate was formed. The suspensionwas stirred for 1 hour at room temperature and an additional hour at 0°C. After washing with cold ethanol the precipitate was dried for 24hours at 50° C. (vacuum).

Yield: 310 g ofmethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate(=68%).

m.p. 97 to 99° C.

EXAMPLE 92-Imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one

190 g (0.380 mol) of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolewere suspended in 2.85 l of ethanol. 31.6 g (0.415 mol) of thiourea and34.8 g of sodium acetate were added. After boiling for about 18 hours(reflux) the reaction mixture was cooled to 0 to 4° C. and stirred for1.5 hours at this temperature. The precipitate was filtered with suctionand washed twice with 250 ml cold ethanol. 1.9 l of water was added tothe residue, the mixture was stirred for 10 minutes and the precipitatewas filtered with suction and dried for 24 hours at 80° C. (vacuum).

Yield: 147 g of2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one(84%);

m.p: 224-227° C.

EXAMPLE 105-[4-[2-(5-Methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzotiophene-7-methyl]-2,4-thiazolidinedione

83.3 g (0.61 mol) of2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-onewere suspended in 2.83 l ethanol. 2.83 l of 2 N hydrochloric acid wereadded. The resulting suspension was stirred for 18 hours (reflux). Thesuspension was cooled for 1 hour to 0 to 4° C. and was stirred foranother 2 hours at this temperature. The precipitate was filtered withsuction and washed twice with 285 ml of ethanol. 2.83 l of water wasadded to the residue, the suspension was stirred for 30 minutes, theprecipitate was filtered with suction and washed with 2 l of water. Theprecipitate was dried for 24 hours at 80° C. and then solved in 545 mlDMF (at 85 to 90° C.). 4.95 l of ethanol (25° C.) were added to thesolution. The resulting suspension was stirred for 2 hours at 0 to 4° C.The precipitate was filtered with suction, washed with 270 ml of coldethanol and dried at 80° C. for 24 hours (vacuum).

Yield: 246 g of5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione(87%);

MP: 224-227° C.

EXAMPLE 115-[4-[2-(5-Methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione-Na-salt

(5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}-2,4-thiazolidinedione)(5.8 g) was dissolved in hot THF (87 ml). A solution of sodium hydroxide(0.5 g) in water (6 ml) was added, and the solution was cooled to roomtemperature. Another portion (87 ml) of THF was given to the solution,and after a short time a crystallization was observed 150 ml of thesolvent was distilled off in the heat The suspension was cooled to about0° C. and was stirred for further 2 hours. The solid was filtered anddried at 80° C.

Yield: 5.6 g of5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione-Na-salt(93%);

MP: >300° C. (decomposition).

What is claimed is:
 1. The process of producing the product4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole byreacting a compound of formula I

with a mesylate of formula V

under basic conditions to form said product.
 2. The process of claim 1,wherein 4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazoleis converted into5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleby nitration.
 3. The process according to claim 2, wherein5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleis converted into of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleby hydrogenation.
 4. The process according to claim 3, wherein5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazoleis converted intomethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionateby reaction with HHal/NaNO₂ followed by reaction withCH═CHCOOCH₃/Cu(I)Hal, wherein Hal is Br or Cl.
 5. The process accordingto claim 4, whereinmethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionateis converted into2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-oneby reaction with thiourea.
 6. The process according to claim 5, wherein2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-oneis converted into5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedioneby reaction under acid conditions.
 7. The process for preparing5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedionecomprising a) conversion of a compound of the formula I

 into 4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole byreaction of a compound of formula I with a mesylate of formula V

 under basic conditions; followed by b) nitration of4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole to give5-methyl-4-[2-(7-nitro-benzotiophene-4-yloxy)-ethyl]-2-phenyl-oxazole;c) hydrogenation of5-methyl-4-[2-(7-nitro-benzothiophene-4-yl)-ethyl]-2-phenyl-oxazole togive5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole;followed by d) reaction of5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazolewith HHal/NaNO₂ and CH═CHCOOCH₃/Cu(I)Hal, wherein Hal is Br or Cl togivemethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate;followed by e) reaction ofmethyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionatewith thiourea to give2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one;followed by f) reaction of2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-oneunder acid conditions to give5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione;and g) optionally followed by reaction of5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinoneunder basic conditions to give5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione-Na-salt.8. The compound comprising5-[4-[2-(5-Methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione-Na-salt.